Novel and synergistic therapeutic combinations are desirable for the treatment of metastatic breast cancer, prostate cancer, Hodgkin's lymphoma, and other cancers, many of which are currently incurable with standard multimodality therapy. High incidence of p53 mutations and bcl-2 protein over-expression in breast cancer increase resistance to chemotherapy and radiotherapy. Systemic, tumor-targeted radioimmunotherapy (RIT) has the potential to target tissue specifically and to deliver cancer-specific cytotoxic antibodies to widespread metastatic foci. However, studies in a human breast cancer xenograft model demonstrate that RIT, as a single agent, typically does not cure the tumors. Tumor penetration of radiolabeled antibodies may be non-uniform and may not be sufficient in all regions of the tumor to provide cure. The combination of RIT with other therapeutic modalities is currently being utilized, but the additional chemotherapy or external radiotherapy increases the risk of bone marrow toxicity, the major dose-limiting factor in RIT.
Antiangiogenic agents have been proposed as a treatment for tumors. These agents target genetically normal endothelial cells, which proliferate at a much higher rate during tumor angiogenesis compared to very low endothelial turnover rates in normal tissues. Antiangiogenic agents have been shown to increase therapeutic efficacy in conjunction with other chemotherapeutic agents and when used in combination with external radiotherapy. The αvβ3 integrin receptor, which binds several ligands via an RGD amino acid sequence, is expressed in normal vasculature, but is highly expressed on growing tumor vasculature, making it a potential target for antiangiogenic agents. High expression and activation of the αvβ3 integrin has also been correlated with the more metastatic and invasive breast tumors. Inhibition of αvβ3 activity by monoclonal antibody (MAb) and cyclic RGD pentapeptides has been shown to induce endothelial apoptosis, inhibit angiogenesis, and increase endothelial monolayer permeability. Inhibition of αvβ3 activity has been associated with decreased tumor growth in breast cancer xenografts and melanoma xenografts. Synergy of cyclic RGD pentapeptide with antibody IL-2 fusion protein has resulted in increased efficacy of therapy in murine models of melanoma, colon carcinoma and neuroblastoma. Selective tumor uptake has been demonstrated with radiolabeled cyclic RGD pentapeptides.